Parasitic helminth infections in animals, including humans, are typically treated by chemical drugs. One disadvantage with chemical drugs is that they must be administered often. For example, dogs susceptible to heartworm are typically treated monthly. Repeated administration of drugs, however, often leads to the development of resistant helminth strains that no longer respond to treatment. Furthermore, many of the chemical drugs cause harmful side effects in the animals being treated, and as larger doses become required due to the build up of resistance, the side effects become even greater. Moreover, a number of drugs only treat symptoms of a parasitic disease but are unable to prevent infection by the parasitic helminth.
An alternative method to prevent parasitic helminth infection includes administering a vaccine against a parasitic helminth. Although many investigators have tried to develop vaccines based on specific antigens, it is well understood that the ability of an antigen to stimulate antibody production does not necessarily correlate with the ability of the antigen to stimulate an immune response capable of protecting an animal from infection, particularly in the case of parasitic helminths. Although a number of prominent antigens have been identified in several parasitic helminths, including in Dirofilaria, there is yet to be a commercially available vaccine developed for any parasitic helminth.
As an example of the complexity of parasitic helminths, the life cycle of D. immitis, the helminth that causes heartworm, includes a variety of life forms, each of which presents different targets. and challenges, for immunization. In a mosquito, D. immitis microfilariae go through two larval stages (L1 and L2) and become mature third stage larvae (L3), which can then be transmitted back to the dog. In a dog, the L3 molt to the fourth larval stage (L4), and subsequently to the fifth stage, or immature adults. The immature adults migrate to the heart and pulmonary arteries, where they mature to adult heartworms. Adult heartworms are quite large and preferentially inhabit the heart and pulmonary arteries of an animal. Sexually mature adults, after mating, produce microfilariae which traverse capillary beds and circulate in the vascular system of the dog.
In particular, heartworm is a major problem in dogs, which typically cannot even develop immunity upon infection (i.e., dogs can become reinfected even after being cured by chemotherapy), and is becoming increasingly widespread in other companion animals, such as cats and ferrets. Heartworm infections have also been reported in humans.
Prior investigators have identified yeast thiol specific antioxidants (TSAs), as well as cloning several mammalian TSA genes, a protozoan TSA gene and a partial nucleic acid sequence of an adult Onchocerca TSA gene; see, for example, Chandrashekar et al., Genbank Accession No. U09385; Yamamoto et al, 1989, Gene 80, 337-343, Torian et al., 1990, Proc. Natl. Acad. Sci. USA 87, 6358-6362, Reed et al., 1992, Infection and Immunity. 60, 542-549, Ramussen et al, 1992, Electrophoresis 13, 960-969, Tannich et al., 1993, Trop. Med. Parasitol. 44, 116-118, Prosperi et al., 1993, J. Biol. Chem. 268, 11050-11056, Ishii et al., 1993, J. Biol. Chem. 268, 18633-18636, Chae et al., 1993, J. Biol. Chem. 268, 16815-16821, Ishii et al., 1993, J. Biol. Chem. 268, 18633-18636, Chae et al., 1994, Proc. Natl. Acad. Sci. USA 91, 7022-7026, Kawai et al, 1994, J. Biochem. 115, 641-643, Chae et al, 1994, Proc. Natl. Acad. Sci. USA 91, 7017-7021 and Chae et al, 1994, Biofactors 4, 177-180. Although yeast, human and bovine cortex TSAs has been shown to have thiol-dependent reductase activity (see, for example, Sauri et al, 1995, Biochem. Biophys. Res. Comm. 208, 964-969; Watabe et al, 1995, Biochem. Biophys. Res. Comm. 213, 1010-1016), the other TSA genes having been identified by nucleic acid sequence homology. The determination of these sequences, however, does not indicate or suggest the cloning of novel larval parasitic helminth TSA genes.
As such, there remains a need to identify an efficacious composition that protects animals against diseases caused by parasitic helminths and that, preferably, also protects animals from infection by such helminths.